Monday, May 26, 2008

Centromere DNA

During mitosis in eukaryotic cells the chromosomes are duplicated and the two sister chromosomes separate and move to opposite ends of the dividing cell. This segregation is controlled by spindle microtubules that attach to specific regions of the chromsomes called centromeres.

Centromeres are easily seen in the light microscope following chromosome condensation. They appear as a constricted region where the daughter chromosomes remain attached to each other. In non-dividing cells the centromere region is heterochromatic, which means that it remains relatively condensed compared to the rest of the chromatin that contains active genes (euchromatin).

Yeast centromeres are very simple but mammalian centromere DNA has not been extensively characterized because it consists largely of multiple repeats of simple sequence DNA. Because of the repetitive nature of centromeric DNA these region are difficult to clone. They are missing from the human genome database.

54%Nevertheless, we have a pretty good idea of the organization of centromere DNA from the few centromeres that have been sequenced. In humans the dominant repeat is α satellite DNA, a 171 bp sequence that is repeated about 18,000 times at an average centromere. Kinetochore proteins bind to the central region of the centrosome and the spindle microtubules attach to the kinetochore (Cheeseman and Desai, 2008).

Fluorescent hybridization studies with α satellite DNA light up all centromeres on human chromosome indicating an abundance of α satellite DNA at all centromeres. We don't know how much of this DNA is essential for chromosome segregation. There are rare examples of neocentromeres (newly formed centromeres) that have very little α satellite DNA suggesting that much of it is non-essential. Artificial human chromosomes segregate at mitosis with only a few copies of α satellite DNA at their centromeres.

Not all α satellite DNA is associated with functional centromeres since the presence of inactive, nonfunctional centromere sequences in the human genome is well known. (Such as one of the ancestral centromeres associated with the formation of human chromosome 2 from a fusion of two separate primate chromosomes. See Stanyon et al. (2008) for a review of the evolution of primate chromosomes with an emphasis on the formation of new centromeres and the loss of ancient ones.)

There are also at least 68,214 monomeric α satellite sequences in the human genome (Alkan et al. 2007).

Human centromeres range from 0.3Mb to 5Mb in size (Cleveland et al. 2003). If the average centromeric region is 3Mb (3,000 kb) in size then 23 centromeres represents 2% of the entire genome sequence. Not all of this DNA is essential because, among other reasons, there is considerable variation between individuals in the length of a given centromere. Nevertheless, lets assume for the sake of our junk DNA calculation that all of it is essential.

Monomeric α satellite sequences make up about 0.3% of the genome (Alkan et al. 2007). These bits of DNA are almost certainly non-essential "escapees" from centromeric regions or fossil centromeres. The total amount of α satellite DNA in the human genome is between 2% and 5%. The vast majority of these sequences are not in the databases. If we add in the fossil centromeres we can estimate that the total amount of junk α satellite DNA comes to about 1% of the genome.

[Image Credits: The drawing of a centromere is from Alberts et al. (2002) Figure 4-50. The photograph of chromosomes is from Hunt Willard (Schueler et al. (2001)]

5 comments
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The accumulation of satellite DNA at cetromeres (and telomeres) may be, in part, because selection is not as efficacious in regions of low recombination. Therefore, slightly deleterious insertions of repetitive sequence are not purged. That's not to say that some of it is not useful for proper segregation.

Also, some of the most interesting work on mammalian centromeres comes from marsupials, where there are a lot of robertsonian fusions and centromeric shifts.

Selection at a single locus is independent of recombination, but genomes aren't composed of independent loci.

Selection is less efficient in regions of low recombination because of interference between loci. A selective sweep at a locus drives all linked alleles to fixation, regardless of whether they are deleterious of advantageous. Also, the removal of deleterious mutations removes all linked variation, even if they are beneficial alleles (Muller's ratchet).

Therefore, fixing advantageous mutations and purging deleterious ones will be less efficient in regions of low recombination. So, we expect the accumulation of deleterious variants (like repetitive insertions).

Laurence A. Moran

Larry Moran is a Professor in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

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The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

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The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

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My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
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Francis Crick
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Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.